Affinage

NME5

Nucleoside diphosphate kinase 5 · UniProt P56597

Length
212 aa
Mass
24.2 kDa
Annotated
2026-04-29
37 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NME5 is a catalytically inactive member of the NDP kinase family that functions as a structural component of motile cilia and sperm flagella, where it assembles into the radial spoke 1 (RS1) head-neck complex together with DYDC1, DNAJB13, and PPIL6 (PMID:39849482). Loss-of-function mutations in NME5 cause primary ciliary dyskinesia with radial spoke and central pair defects in humans and dogs, and hydrocephalus in knockout mice (PMID:32185794, PMID:31479451, PMID:21746835). In spermatogenesis, NME5 is expressed from spermatogonia through elongated spermatids, localizes to the flagellar axoneme, and regulates late spermatid survival by upregulating the antioxidant enzyme GPX-5 to eliminate reactive oxygen species; complete loss of NME5 causes acephalic spermatozoa with disrupted head-tail coupling apparatus and radial spoke defects (PMID:19303412, PMID:41499646). Transcription of NME5 is driven by Sp1 binding to two GC-box elements in its proximal promoter (PMID:22564704).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1998 High

    Identification of NME5 as a novel NDP kinase family member that lacks canonical enzymatic activity established it as a divergent, potentially non-catalytic member of the NME family with testis-specific expression.

    Evidence cDNA cloning, Northern blot, in situ hybridization, and recombinant protein NDPK activity assay in E. coli

    PMID:9742940

    Open questions at the time
    • No structural basis for why NDPK activity is absent
    • Function of the unique 55-amino acid C-terminal extension unknown
  2. 2003 High

    Localization of NME5 to the sperm flagellar axoneme and demonstration that it protects against apoptosis by upregulating GPX-5 linked a non-catalytic NDP kinase family member to both flagellar structure and redox-dependent spermatid survival.

    Evidence Immunofluorescence of sperm flagella (PMID:14499630); overexpression in fibroblasts with GPX-5 activity assays and Bax-induced apoptosis protection (PMID:12788088)

    PMID:12788088 PMID:14499630

    Open questions at the time
    • Mechanism by which NME5 upregulates GPX-5 not determined
    • Whether NME5 has a direct structural role in the axoneme vs. indirect role unclear
  3. 2009 High

    In vivo knockdown in transgenic mice confirmed that NME5 is required for spermatid survival and that this function operates through GPX-5-mediated ROS elimination, establishing a causal loss-of-function relationship.

    Evidence shRNA transgenic mouse with reduced haploid cell numbers, decreased GPX-5 expression and activity

    PMID:19303412

    Open questions at the time
    • Transcriptional vs. post-transcriptional mechanism of GPX-5 regulation not resolved
    • Whether NME5 directly binds GPX-5 promoter or acts through intermediaries unknown
  4. 2011 High

    Nme5 knockout mice developing hydrocephalus from dysfunctional motile cilia extended NME5's role beyond spermatogenesis to general motile cilia function.

    Evidence Knockout mouse generation with veterinary pathological analysis of cilia

    PMID:21746835

    Open questions at the time
    • Specific ciliary ultrastructural defect not characterized
    • Whether hydrocephalus reflects ependymal cilia or other motile cilia dysfunction not distinguished
  5. 2012 Medium

    Characterization of the NME5 promoter identified Sp1 as the key transcriptional activator acting through two GC-boxes, providing a regulatory framework for tissue-specific expression; separately, NME5 was implicated in gemcitabine resistance via NF-κB binding in pancreatic cancer cells.

    Evidence EMSA, ChIP, and promoter-reporter assays for Sp1 (PMID:22564704); Co-IP, siRNA, and overexpression with apoptosis/cell cycle assays for NF-κB interaction (PMID:22325559)

    PMID:22325559 PMID:22564704

    Open questions at the time
    • NF-κB interaction identified by single Co-IP without reciprocal validation
    • How Sp1-driven transcription achieves testis-enriched expression not explained
    • Cancer role not independently replicated
  6. 2019 High

    A frameshift variant in NME5 causing primary ciliary dyskinesia in dogs, with confirmed absence of protein by IHC, established NME5 as a bona fide PCD gene across species.

    Evidence Whole genome sequencing, linkage/homozygosity mapping, immunohistochemistry in Alaskan Malamute dogs; corroborated by Nme5-/- mouse phenotype

    PMID:31479451

    Open questions at the time
    • Whether NME5 loss affects specific axonemal substructures (e.g., radial spokes) not yet determined in this model
  7. 2020 High

    Identification of a human nonsense NME5 variant causing PCD with radial spoke and central pair defects, validated by zebrafish morpholino, confirmed NME5 as a human PCD-causative gene and localized its structural requirement to the RS/CP apparatus.

    Evidence Whole exome sequencing in human family, morpholino knockdown in zebrafish with cilia phenotype analysis

    PMID:32185794

    Open questions at the time
    • Precise position of NME5 within the radial spoke complex not determined
    • Rescue experiment not performed
  8. 2025 Medium

    NME5 was placed within the RS1 head-neck complex alongside DYDC1, DNAJB13, and PPIL6, while separately a human frameshift variant revealed that NME5 loss causes acephalic spermatozoa with disrupted HTCA and mitochondrial sheath, broadening the phenotypic spectrum of NME5 deficiency.

    Evidence Protein mass spectrometry, electron microscopy, and immunofluorescence in Iqub-/- mice and human sperm (PMID:39849482); WES, TEM, and immunofluorescence in human ASS patients (PMID:41499646)

    PMID:39849482 PMID:41499646

    Open questions at the time
    • Direct protein-protein interactions between NME5 and other RS1 components not biochemically validated
    • How NME5 contributes to HTCA integrity vs. flagellar radial spoke assembly is unclear
    • No structural model of NME5 within the RS1 complex

Open questions

Synthesis pass · forward-looking unresolved questions
  • The precise molecular function of NME5 within the RS1 complex — whether it acts as a scaffold, adaptor, or has an unrecognized enzymatic activity — and the mechanism by which it regulates GPX-5 expression remain unresolved.
  • No crystal or cryo-EM structure of NME5 or the RS1 head-neck complex
  • Mechanism linking NME5 to GPX-5 transcriptional regulation not defined
  • Whether NME5 has any catalytic activity (e.g., exonuclease) remains unconfirmed by primary data

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005929 cilium 4 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-1474165 Reproduction 3
Partners
DNAJB13DYDC1GPX5PPIL6SP1
Complex memberships
Radial spoke 1 (RS1) head-neck complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 NME5 (Nm23-H5) was identified as a new member of the nm23/NDP kinase gene family, specifically and highly expressed in testis spermatogonia and early spermatocytes. The recombinant protein expressed in E. coli did not exhibit NDP kinase activity under standard assay conditions, suggesting it lacks canonical enzymatic activity despite possessing conserved NDP kinase residues plus a unique 55-amino acid C-terminal extension. cDNA cloning, Northern blot, in situ hybridization, heterologous expression in E. coli with NDP kinase activity assay FEBS letters High 9742940
2003 Nm23-H5 protein localizes to the flagella of spermatids and spermatozoa, adjacent to the central pair and outer doublets of axonemal microtubules, implicating it in the phosphotransfer network for flagellar movement. Immunohistochemistry, immunofluorescence microscopy, Western blotting of sperm extracts Experimental cell research High 14499630
2003 Murine Nm23-M5 (ortholog of NME5) is expressed in late spermatids and overexpression in fibroblasts protects against Bax-induced apoptosis by elevating antioxidant enzymes, particularly glutathione peroxidase 5 (GPX-5), reducing reactive oxygen species. Heterologous yeast expression, overexpression in fibroblasts, antioxidant enzyme activity assays, RT-PCR, in situ hybridization Biochemical and biophysical research communications Medium 12788088
2009 Knockdown of Nm23-M5 in transgenic mice using shRNA reduced haploid cell numbers during spermiogenesis and decreased GPX-5 expression and activity, establishing that NME5 regulates spermatid survival through control of GPX-5 levels to eliminate reactive oxygen species. shRNA transgenic mouse knockdown, Northern blot, Western blot, GPX-5 activity assay FEBS letters High 19303412
2011 Nme5 knockout mice develop congenital hydrocephalus, and the underlying pathogenetic mechanism is dysfunctional motile cilia, as determined by pathological analysis of the genetically engineered mouse lines. Knockout mouse generation, veterinary pathological analysis, cilia functional assessment Veterinary pathology High 21746835
2012 NME5 contributes to innate gemcitabine resistance in pancreatic cancer cells by attenuating apoptosis and cell cycle arrest; NME5 was shown to directly bind NF-κB and regulate its expression, operating in an NF-κB-dependent manner. siRNA knockdown, overexpression, apoptosis assays, cell cycle analysis, co-immunoprecipitation (NME5-NF-κB binding), gene arrays The FEBS journal Medium 22325559
2012 The NME5 promoter was characterized: the transcription start site is at -35 bp relative to the ATG, and two GC-boxes at -300 bp and -323 bp are required for promoter activity. Transcription factor Sp1 binds these GC-boxes and transactivates NME5 expression. 5' deletion analysis, EMSA, ChIP, Sp1 overexpression, promoter-reporter assays Gene Medium 22564704
2017 NME5 (along with NME1, NME7, and NME8) exhibits a 3'-5' exonuclease activity, suggesting a role in DNA proofreading and repair within the NME family. Review citing biochemical activity data for NME family members Laboratory investigation Low 29058704
2019 A frameshift variant (c.43delA) in NME5 causes primary ciliary dyskinesia in Alaskan Malamute dogs, with immunohistochemistry demonstrating complete absence of NME5 protein from nasal epithelia of affected animals; Nme5-/- knockout mice exhibit hydrocephalus and sperm flagellar defects. Whole genome sequencing, linkage/homozygosity mapping, immunohistochemistry, knockout mouse phenotyping PLoS genetics High 31479451
2020 A homozygous nonsense variant (c.572G>A; p.Trp191*) in NME5 causes human primary ciliary dyskinesia with radial spoke and central pair defects; morpholino knockdown of nme5 in zebrafish embryos reproduced motile cilia defects, establishing NME5 as a PCD-causative gene in humans. Whole exome sequencing, morpholino knockdown in zebrafish, cilia phenotype analysis Clinical genetics High 32185794
2025 A homozygous frameshift variant in NME5 (c.163delA) causes acephalic spermatozoa syndrome (ASS) with complete loss of NME5 protein; ultrastructural analysis showed abnormalities in the head-tail coupling apparatus (HTCA), mitochondrial sheath, radial spokes, and microtubules; SPATA6 (HTCA marker) was nearly absent from patient sperm; NME5 is predominantly expressed from round to elongated spermatids. Whole exome sequencing, immunofluorescence, transmission electron microscopy, Western blot, expression profiling Clinical genetics Medium 41499646
2025 NME5 is a component of the radial spoke 1 (RS1) head-neck complex in sperm flagella, assembling together with DYDC1, DNAJB13, and PPIL6 into this structural unit; loss of RS1 (but not RS2 or RS3) accompanies IQUB deficiency, and NME5 was identified by protein mass spectrometry as a critical RS1 component in humans and mice. Protein mass spectrometry, Western blot, immunofluorescence, electron microscopy, bioinformatic structural modeling, Iqub-/- mice Cell communication and signaling Medium 39849482

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Deregulation of purine metabolism in Alzheimer's disease. Neurobiology of aging 130 25311278
2014 Coordinated genomic control of ciliogenesis and cell movement by RFX2. eLife 119 24424412
2011 Congenital hydrocephalus in genetically engineered mice. Veterinary pathology 115 21746835
2009 Nme protein family evolutionary history, a vertebrate perspective. BMC evolutionary biology 98 19852809
1998 A new human nm23 homologue (nm23-H5) specifically expressed in testis germinal cells. FEBS letters 98 9742940
2015 RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes. American journal of human genetics 72 26073779
2015 Purine metabolism gene deregulation in Parkinson's disease. Neuropathology and applied neurobiology 66 25597950
2012 Simultaneous modulation of the intrinsic and extrinsic pathways by simvastatin in mediating prostate cancer cell apoptosis. BMC cancer 65 22974127
2017 Nuclear functions of NME proteins. Laboratory investigation; a journal of technical methods and pathology 64 29058704
2013 Additive effect of the AZGP1, PIP, S100A8 and UBE2C molecular biomarkers improves outcome prediction in breast carcinoma. International journal of cancer 59 24114735
2008 Genes involved in differentiation, stem cell renewal, and tumorigenesis are modulated in telomerase-immortalized human urothelial cells. Molecular cancer research : MCR 46 18644980
2003 Nm23/NDP kinases in human male germ cells: role in spermiogenesis and sperm motility? Experimental cell research 45 14499630
2020 A nonsense variant in NME5 causes human primary ciliary dyskinesia with radial spoke defects. Clinical genetics 31 32185794
2019 Genome-wide scans identify known and novel regions associated with prolificacy and reproduction traits in a sub-Saharan African indigenous sheep (Ovis aries). Mammalian genome : official journal of the International Mammalian Genome Society 26 31758253
2021 Combined photodynamic therapy with chloroaluminum phthalocyanine and doxorubicin nanoemulsions in breast cancer model. Journal of photochemistry and photobiology. B, Biology 24 33845338
2003 Cloning, sequencing, and characterization of the murine nm23-M5 gene during mouse spermatogenesis and spermiogenesis. Biochemical and biophysical research communications 24 12788088
2009 Nm23-M5 mediates round and elongated spermatid survival by regulating GPX-5 levels. FEBS letters 23 19303412
2019 NME5 frameshift variant in Alaskan Malamutes with primary ciliary dyskinesia. PLoS genetics 22 31479451
2016 A Study of Differential Expression of Testicular Genes in Various Reproductive Phases of Hemidactylus flaviviridis (Wall Lizard) to Derive Their Association with Onset of Spermatogenesis and Its Relevance to Mammals. PloS one 18 26963275
2020 Comprehensive analysis of the NME gene family functions in breast cancer. Translational cancer research 14 35117245
2012 Identification of NME5 as a contributor to innate resistance to gemcitabine in pancreatic cancer cells. The FEBS journal 13 22325559
2000 The nucleoside diphosphate kinase activity of DRnm23 is not required for inhibition of differentiation and induction of apoptosis in 32Dcl3 myeloid precursor cells. Experimental cell research 13 10837140
2012 Transactivation of the human NME5 gene by Sp1 in pancreatic cancer cells. Gene 12 22564704
2008 Molecular and cytogenetic characterization of repetitive DNA in the Antarctic polyplacophoran Nuttallochiton mirandus. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 12 18679814
2023 Primary Ciliary Dyskinesia Patient-Specific hiPSC-Derived Airway Epithelium in Air-Liquid Interface Culture Recapitulates Disease Specific Phenotypes In Vitro. Cells 10 37296588
2020 Overexpression of B7-H4 promotes renal cell carcinoma progression by recruiting tumor-associated neutrophils via upregulation of CXCL8. Oncology letters 7 32724395
2019 Characterization of Nme5-Like Gene/Protein from the Red Alga Chondrus Crispus. Marine drugs 7 31877804
2025 IQUB mutation induces radial spoke 1 deficiency causing asthenozoospermia with normal sperm morphology in humans and mice. Cell communication and signaling : CCS 5 39849482
2020 Generation of two hiPSC clones (MHHi019-A, MHHi019-B) from a primary ciliary dyskinesia patient carrying a homozygous deletion in the NME5 gene (c.415delA (p.Ile139Tyrfs*8)). Stem cell research 5 32950024
2023 Clinical Manifestations and Genotype of Primary Ciliary Dyskinesia Diagnosed in Korea: Multicenter Study. Allergy, asthma & immunology research 4 37957793
2024 Mitochondrial NME6: A Paradigm Change within the NME/NDP Kinase Protein Family? Cells 3 39120309
2024 Nme8 is essential for protection against chemotherapy drug cisplatin-induced male reproductive toxicity in mice. Cell death & disease 2 39368984
2011 An activity model for novel antidepressants that interact with the serotonin transporter (SERT). Central nervous system agents in medicinal chemistry 2 21919867
2025 Detection of LUAD-Associated Genes Using Wasserstein Distance in Multiomics Feature Selection. Bioengineering (Basel, Switzerland) 1 40722386
2024 Construction of thyroid cancer classification and iodine metabolism related diagnostic model using thyroid differentiation score and bioinformation. Medicine 1 39252309
2025 In Silico Analysis of the Role of Estrogen Signaling in the Expression of Metabolic Genes in Breast Cancer. Asian Pacific journal of cancer prevention : APJCP 0 41459856
2025 Discovery of a Pathogenic NME5 Variant Underlying Acephalic Spermatozoa Syndrome: Unraveling a Novel Genotype-Phenotype Association in Male Infertility. Clinical genetics 0 41499646